Kidney disease in antiretroviral-naïve HIV-positive adults with high CD4 counts: prevalence and predictors of kidney disease at enrolment in the INSIGHT Strategic Timing of AntiRetroviral Treatment (START) trial.

OBJECTIVES: HIV infection has been associated with an increased risk of chronic kidney disease (CKD). Little is known about the prevalence of CKD in individuals with high CD4 cell counts prior to initiation of antiretroviral therapy (ART). We sought to address this knowledge gap. METHODS: We describe the prevalence of CKD among 4637 ART-naïve adults (mean age 36.8 years) with CD4 cell counts > 500 cells/µL at enrolment in the Strategic Timing of AntiRetroviral Treatment (START) study. CKD was defined by estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m(2) and/or dipstick urine protein ≥ 1+. Logistic regression was used to identify baseline characteristics associated with CKD. RESULTS: Among 286 [6.2%; 95% confidence interval (CI) 5.5%, 6.9%] participants with CKD, the majority had isolated proteinuria. A total of 268 participants had urine protein ≥ 1+, including 41 with urine protein ≥ 2+. Only 22 participants (0.5%) had an estimated glomerular filtration rate < 60 mL/min/1.73 m(2) , including four who also had proteinuria. Baseline characteristics independently associated with CKD included diabetes [adjusted odds ratio (aOR) 1.73; 95% CI 1.05, 2.85], hypertension (aOR 1.82; 95% CI 1.38, 2.38), and race/ethnicity (aOR 0.59; 95% CI 0.37, 0.93 for Hispanic vs. white). CONCLUSIONS: We observed a low prevalence of CKD associated with traditional CKD risk factors among ART-naïve clinical trial participants with CD4 cell counts > 500 cells/µL.

Glomerular filtration rate estimated using creatinine, cystatin C or both markers and the risk of clinical events in HIV-infected individuals.

OBJECTIVES: The accuracy and precision of glomerular filtration rate (GFR) estimating equations based on plasma creatinine (GFR(cr)), cystatin C (GFR(cys)) and the combination of these markers (GFR(cr-cys)) have recently been assessed in HIV-infected individuals. We assessed the associations of GFR, estimated by these three equations, with clinical events in HIV-infected individuals. METHODS: We compared the associations of baseline GFR(cr), GFR(cys) and GFR(cr-cys) [using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations] with mortality, cardiovascular events (CVEs) and opportunistic diseases (ODs) in the Strategies for the Management of Antiretroviral Therapy (SMART) study. We used Cox proportional hazards models to estimate unadjusted and adjusted hazard ratios per standard deviation (SD) change in GFR. RESULTS: A total of 4614 subjects from the SMART trial with available baseline creatinine and cystatin C data were included in this analysis. Of these, 99 died, 111 had a CVE and 121 had an OD. GFR(cys) was weakly to moderately correlated with HIV RNA, CD4 cell count, high-sensitivity C-reactive protein, interleukin-6, and D-dimer, while GFR(cr) had little or no correlation with these factors. GFR(cys) had the strongest associations with the three clinical outcomes, followed closely by GFR(cr-cys), with GFR(cr) having the weakest associations with clinical outcomes. In a model adjusting for demographics, cardiovascular risk factors, HIV-related factors and inflammation markers, a 1-SD lower GFR(cys) was associated with a 55% [95% confidence interval (CI) 27-90%] increased risk of mortality, a 21% (95% CI 0-47%) increased risk of CVE, and a 22% (95% CI 0-48%) increased risk of OD. CONCLUSIONS: Of the three CKD-EPI GFR equations, GFR(cys) had the strongest associations with mortality, CVE and OD.

The use of feathers in monitoring bioaccumulation of metals and metalloids in the South African endangered African grass-owl (Tyto capensis).

Few studies have quantified metals in South African species and no published data on residues specifically in South African owl feathers exist. Tyto capensis is listed as vulnerable within South Africa, making it preferable to use a non-invasive technique to determine metal bioaccumulation for this species. Comparisons are made with the cosmopolitan T. alba to determine whether this species could be used as a surrogate. Concentrations of various metals were thus determined in feathers of the two species and compared with liver and muscle samples. Samples were taken from 119 owls collected as road kill along a national road. A comparison of concentrations in feathers revealed similarly higher concentrations of aluminium, antimony, lead, nickel, and strontium, whereas concentrations of chromium, copper, iron, manganese, selenium, titanium and zinc were similarly higher in internal tissues for both species. Metal concentrations of owls were comparable to those reported in literature and below toxic levels, suggesting that these metals were not likely to impact the owls. Further regressions between feathers and corresponding livers were examined to determine if feathers were indicative of internal metal burdens. Significant positive relationships were found for aluminium, copper, lead, nickel and vanadium in T. alba and nickel, manganese and vanadium in T. capensis. Preliminary results support the feasibility of using feathers as non-destructive indicators of environmental contamination in T. capensis although caution needs to be taken when interpreting the results.

Determinants of incident chronic kidney disease and progression in a cohort of HIV-infected persons with unrestricted access to health care.

OBJECTIVES: As socioeconomic factors may impact the risk of chronic kidney disease (CKD), we evaluated the incidence and risk factors of incident CKD among an HIV-infected cohort with universal access to health care and minimal injecting drug use (IDU). METHODS: Incident CKD was defined as an estimated glomerular filteration rate (eGFR) <60 ml/min/1.73 m(2) for ≥ 90 days. eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. Rates were calculated per 1000 person-years (PY). Associations with outcomes were assessed using two separate Cox proportional hazard models, adjusting for baseline and time-updated covariates. RESULTS: Among 3360 participants [median age 29 years; 92% male; 44% African American (AA)] contributing 23,091 PY of follow-up, 116 developed incident CKD [5.0/1000 PY; 95% confidence interval (CI) 4.2-6.0/1000 PY]. The median first eGFR value was 97.0 mL/min/1.73 m(2) [interquartile range (IQR) 85.3-110.1 mL/min/1.73 m(2)]. Baseline factors associated with CKD included older age, lower CD4 count at HIV diagnosis [compared with CD4 count ≥ 500 cells/µL, hazard ratio (HR) 2.1 (95% CI 1.2-3.8) for CD4 count 350-499 cells/µL; HR 3.6 (95% CI 2.0-6.3) for CD4 count 201-349 cells/µL; HR 4.3 (95% CI 2.0-9.4) for CD4 count ≤ 200 cells/µL], and HIV diagnosis in the pre-highly active antiretroviral therapy (HAART) era. In the time-updated model, low nadir CD4 counts, diabetes, hepatitis B, hypertension and less HAART use were also associated with CKD. AA ethnicity was not associated with incident CKD in either model. CONCLUSIONS: The low incidence of CKD and the lack of association with ethnicity observed in this study may in part be attributable to unique features of our cohort such as younger age, early HIV diagnosis, minimal IDU, and unrestricted access to care. Lower baseline CD4 counts were significantly associated with incident CKD, suggesting early HIV diagnosis and timely introduction of HAART may reduce the burden of CKD.

Tracheal intubation in the critically ill: a multi-centre national study of practice and complications.

BACKGROUND: Complications associated with tracheal intubation may occur in up to 40% of critically ill patients. Since practice in emergency airway management varies between intensive care units (ICUs) and countries, complication rates may also differ. We undertook a prospective, observational study of tracheal intubation performed by critical care doctors in Scotland to identify practice, complications, and training. METHODS: For 4 months, we collected data on any intubation performed by doctors working in critical care throughout Scotland except those in patients having elective surgery and those carried out before admission to hospital. We used a standardized data form to collect information on pre-induction physical state and organ support, the doctor carrying out the intubation, the techniques and drugs used, and complications noted. RESULTS: Data from 794 intubations were analysed. Seventy per cent occurred in ICU and 18% occurred in emergency departments. The first-time intubation success rate was 91%, no patient required more than three attempts at intubation, and one patient required surgical tracheostomy. Severe hypoxaemia ( <80%) occurred in 22%, severe hypotension (systolic arterial pressure <80 mm Hg) in 20%, and oesophageal intubation in 2%. Three-quarters of intubations were performed by doctors with more than 24 months formal anaesthetic training and all but one doctor with <6 months training had senior supervision. CONCLUSIONS: Tracheal intubation by critical care doctors in Scotland has a higher first-time success rate than described in previous reports of critical care intubation, and technical complications are few. Doctors carrying out intubation had undergone longer formal training in anaesthesia than described previously, and junior trainees are routinely supervised. Despite these good results, further work is necessary to reduce physiological complications and patient morbidity.

Corynebacterium jeikeium native valve endocarditis following femoral access for coronary angiography.

We present a unique case of rapidly fatal native aortic-valve endocarditis due to Corynebacterium jeikeium, with inoculation as a complication of repeated femoral vascular access for coronary angiography.

Serological evidence for an inflammatory response in murine scrapie.

Transmissible spongiform encephalopathies (TSEs) are initiated by a novel kind of agent that produces characteristic degenerative changes in the brain without a detectable systemic inflammatory response or serological changes. A murine scrapie model was evaluated for changes in plasma concentration of serum amyloid P component (SAP), a protein that is up-regulated in infected and/or injured mice during the acute phase response (APR). C57BL10 and IRW mice inoculated with scrapie brain developed clinical scrapie 125-150 days later. At this time, concentration of plasma SAP increased in most of them. The SAP level increased > or =3-fold in >80% of the scrapie-affected C57BL10 mice and IRW male mice. A similar increase was found in <3% of respective nonscrapie control mice. The up-regulation of mouse SAP during clinical scrapie provides evidence for the activation of a systemic APR in TSE, a serological change that may be clinically useful.

HIV-associated nephropathy: case study and review of the literature.

Human immunodeficiency virus type 1 (HIV-1)-seropositive patients are at risk for the development of a variety of acute and chronic renal diseases. The most common cause of chronic renal failure in HIV-1-seropositive patients is HIV-associated nephropathy (HIVAN). HIVAN occurs almost exclusively in black patients and the majority of published cases are of patients who present with acquired immunodeficiency syndrome (AIDS). This disease is currently the third leading cause of end-stage renal disease in blacks aged 20-64. Because HIV-1-seropositive patients may develop a wide variety of acute and chronic renal diseases, definitive diagnosis requires renal biopsy. Emerging data suggest a direct role of HIV-1 infection of kidney cells in the pathogenesis of HIVAN. There have been no well-controlled clinical trials in the treatment of HIVAN. The therapeutic agents with the most promise are angiotensin-converting enzyme inhibitors and antiretroviral medications. Long-term renal prognosis may be changing in the setting of improved aggressive antiretroviral therapy. Patient survival is determined primarily by the stage of HIV-1 infection. In this article, we present the case history of a patient who developed HIVAN. We then review the current literature concerning the epidemiology, differential diagnosis, etiology, and treatment of HIVAN.

Effect of hamster pregnancy on female protein, a homolog of serum amyloid P component.

Pentraxins such as human serum amyloid P component (SAP) and C reactive protein (CRP) represent an ancient family of proteins that are ubiquitous in nature and have evolved with little change in structure or regulation. The pentraxin in the Syrian hamster (Mesocricetus auratus) is unique because it is preferentially expressed in the female at high constitutive levels and accordingly called female protein (FP) or FP(SAP) due to its close homology with human SAP. The high levels of FP in female serum (100-fold greater than male serum) suggested its role in hamster pregnancy, one of the shortest of any eutherian mammal. We determined the serum FP concentration in pregnant Syrian hamsters and found a marked decrease (>80%) at term with the nadir at parturition with subsequent increase. A similar downregulation of FP was found in the normal female Syrian hamster after injury (acute phase response), so in both cases the assumed beneficial effects were achieved with less, rather than more pentraxin, a paradoxical pentraxin response. The fall in serum FP concentration could represent a response to protect the fetus from the high and potentially toxic level of FP normally found in the female, that is harmful because of its association with amyloidosis. An FP that is 97.5% identical to Syrian hamster FP is found in the Turkish hamster (Mesocricetus brandti), although serum levels in females are much lower, and amyloid is very rare. During pregnancy/parturition of Turkish hamsters, the serum level of FP remained remarkably constant. In a more distantly related hamster, the Armenian hamster (Cricetulus migratorius), serum FP actually increased during pregnancy and at parturition in a manner similar to that found in the Armenian hamster during an acute phase response. The heterogeneity of FP kinetics during pregnancy in these three species of hamster indicates pleomorphic gene structure for regulation of their similar FPs, and suggests that this protein may have a different function in the pregnancy of each species.

Estrogen-induced hepatic toxicity and hepatic cancer: differences between two closely related hamster species.

AIMS/BACKGROUND: Estrogen is known to affect hepatobiliary function; however, it is unusual for high serum levels of estrogen to actually result in clinically detectable hyperbilirubinemia. Women affected by cholestatic jaundice during pregnancy share this genetic susceptibility with two Cricetulus hamsters, the Armenian hamster (Cricetulus migratorius) and the Chinese hamster (Cricetulus griseus). Nevertheless, the pathophysiologic process responsible for this estrogen induced icterus may be different in women and hamsters. The present study compares various facets of estrogen-induced icterus in these two closely related hamsters. METHODS: Hamsters were injected with various estrogens and the acute and chronic effects on liver were monitored by measuring changes in serum constituents and by observing changes in hepatic structure as seen grossly and by light and electron microscopy. RESULTS: In previous studies, hepatic tumors developed in most Armenian hamsters after chronic estrogen treatment, but in the present study, the livers of Chinese hamsters were remarkably free of neoplastic change under similar conditions. Also, when compared with the responses in the Armenian hamsters, signs of hepatic destruction and regeneration were less prevalent in estrogen-treated Chinese hamsters, and they were less susceptible to the effects of estrogen (because larger doses of estrogen were required to produce icterus and the bilirubin levels were lower and of shorter duration). In contrast to the findings in Armenian hamsters, bile canaliculi were severely affected in livers of estrogen-treated Chinese hamsters, and hepatic microvesicular steatosis, indicative of an unusual lipodystrophy caused by estrogen, was prominent. An additional lesion peculiar to the Chinese hamster was striking sinusoidal dilatation, which may be analogous to the oral contraceptive-induced sinusoidal dilatation in humans. CONCLUSIONS: Although these two hamster species are genetically similar, the genes activated by the estrogen receptor show remarkable heterogeneity when their respective livers are examined. Comparisons within these species may provide information about the specific gene activation responsible for particular pathologic events.

Design of potent selective zinc-mediated serine protease inhibitors.

Many serine proteases are targets for therapeutic intervention because they often play key roles in disease. Small molecule inhibitors of serine proteases with high affinity are especially interesting as they could be used as scaffolds from which to develop drugs selective for protease targets. One such inhibitor is bis(5-amidino-2-benzimidazolyl)methane (BABIM), standing out as the best inhibitor of trypsin (by a factor of over 100) in a series of over 60 relatively closely related analogues. By probing the structural basis of inhibition, we discovered, using crystallographic methods, a new mode of high-affinity binding in which a Zn2+ ion is tetrahedrally coordinated between two chelating nitrogens of BABIM and two active site residues, His57 and Ser 195. Zn2+, at subphysiological levels, enhances inhibition by over 10(3)-fold. The distinct Zn2+ coordination geometry implies a strong dependence of affinity on substituents. This unique structural paradigm has enabled development of potent, highly selective, Zn2+-dependent inhibitors of several therapeutically important serine proteases, using a physiologically ubiquitous metal ion.

Female protein, amyloidosis, and hormonal carcinogenesis in Turkish hamster: differences from Syrian hamster.

The Syrian hamster (Mesocricetus auratus) has been widely used as an experimental animal and is a unique model for three sex hormone-regulated events: 1) estrogen-initiated renal carcinogenesis, 2) sex-limited expression of amyloidosis, a ubiquitous disease, and 3) sex hormone control of a serum amyloid P component (SAP) called female protein (FP). In this study, we evaluated the closely related Turkish hamster (Mesocricetus brandti) for these three events and found some very different responses: 1) estrogen-initiated renal carcinogenesis was not found in Turkish hamster, 2) amyloidosis was not sex limited and actually was a rare disease in the Turkish hamster, and 3) Turkish hamsters did express a sex-limited SAP-FP in serum that was antigenically identical and structurally very similar (97.5%) to Syrian hamster SAP-FP. However, acute phase regulation of SAP-FP synthesis was different, and serum levels of this pentraxin were much lower than those found in the Syrian hamster. On the other hand, in contrast to findings in the Syrian hamster, hepatic tumors were relatively common in normal and especially in estrogen-treated Turkish hamsters. Therefore, although they are closely related, these two Mesocricetus hamster species have markedly dissimilar responses to sex hormones.

Assessment of postoperative pain management: patient satisfaction and perceived helpfulness.

OBJECTIVE: Increasing attention has been given to the assessment of patient satisfaction as a way to monitor quality of care in hospital settings. Postoperative patient satisfaction has been thought to be related to level of pain intensity, expectations of outcome, perceived concern by the staff, and helpfulness of treatments. The aim of this study is to develop a simple, reliable measure to assess pain and satisfaction in postsurgical patients and to examine factors related to patient satisfaction. DESIGN: A satisfaction questionnaire was developed for this study and administered to 119 patients who had undergone a major orthopedic surgical procedure. The majority of the patients were diagnosed with osteoarthritis and reported moderate to severe preoperative pain. The 13-item measure was found to be reliable (test-retest r = .86; interexaminer r = .98), valid (exploratory factor analyses; intercorrelations), and easy to administer. RESULTS: Results showed that the majority of the patients were satisfied with their care (91%), postoperative pain intensity (94%), and the way they were treated by the physicians and nurses (98%). Patients with low postoperative pain ratings who perceived that the physicians and nurses showed concern with how much pain they were feeling reported greatest satisfaction with their care (p < .001). In general, lower postoperative pain ratings were the best predictors of satisfaction and helpfulness of treatment. Preoperative pain status, expected level of postoperative pain, and time waiting for pain medication after a request was made were not significantly correlated with ratings of postoperative pain or satisfaction. CONCLUSIONS: These results highlight the important influence of adequate treatment of postoperative pain and perceived concern by the hospital staff on patient satisfaction.

Electrophoretic polymorphism of a hamster pentraxin, female protein (amyloid P component).

Serum amyloid P protein (SAP) is a ubiquitous vertebrate protein distinguished by its conservative evolution and paucity of polymorphic forms. The SAP homologue in the Syrian hamster (Mesocricetus auratus), called Female Protein [FP(SAP)] is unique because its synthesis is controlled by sex hormones. These observations were limited to the commercially available standard Syrian hamsters that are descendants of three littermates captured in Syria in 1930. The authors examined FP(SAP) expression in nine inbred lines of Syrian hamsters that were derived from 12 wild hamsters captured in 1971. In general, regulation of FP(SAP) was similar in the new wild hamster strains, although a novel electrophoretically slower FP(SAP) was found in three of the strains. The slow FP(SAP) was not distinguished by size, antigenicity, binding capacity, or regulation. The electrophoretic difference was still apparent after deglycosylation. Hybrid offspring coexpressed both fast and slow FP monomers and formed a unique hybrid pentamer that had a new mobility between the fast and slow parent FP(SAP). The origin of this unusual polymorphism could be related to the amyloidogenesis associated with expression of FP(SAP) in the standard Syrian hamster.

Effects of stress inoculation training on athletes' postsurgical pain and rehabilitation after orthopedic injury.

The efficacy of a cognitive-behavioral intervention (stress inoculation training; SIT) for postsurgical anxiety, pain, and physical rehabilitation in injured athletes was tested. Sixty male athletes who underwent arthroscopic surgery for miniscus injury in 1 knee were randomly assigned to either treatment (SIT and physical therapy) or control (physical therapy only) conditions. Results showed that participants in the treatment group demonstrated significantly less postsurgical pain and anxiety during the rehabilitation process, compared with controls. Additionally, treated participants required fewer days to return to criterion physical functioning, compared with nontreated participants.

The changing workforce: the role of health psychology.

Because the federal government is the largest payer of all health costs, unbridled increases in the health workforce have profound fiscal implications. Recent efforts to control health spending through modifications of health delivery systems are related to the consequences of the unlimited production of health professionals. However, the federal government has established processes to review physician workforce changes, and these mechanisms have become important in accessing federal training monies. Psychologists have no concerted workforce policy and receive little federal training money. Moreover, other health professionals have attained statutory authority to perform and provide the same services as psychologists. This diffusion of professional functions impedes the ability to assess the status of the workforce and the development of psychology as a health profession.

Immune response in the hamster: definition of a novel IgG not expressed in all hamster strains.

A new IgG isotype is described in serum from Syrian hamsters. This 7S-IgG is called IgG3 and was isolated from IgG1 and IgG2 because of its great affinity for protein A. The unique antigenic determinants of IgG3 were identified with a specific rabbit antisera. IgG3 is the least expressed IgG subclass in Syrian hamsters, but serum levels increase more than 10-fold after immunization or infection. Although found in all tested outbred strains, IgG3 is expressed in only some of the commercially available inbred strains of Syrian hamsters. Five inbred hamster strains were examined, and in three strains (CB, LHC and MHA) IgG3 was not detected in normal serum or in immune serum, indicating serum levels at least 100-fold less than other normal inbred/outbred hamsters. The results of breeding experiments suggests a single gene defect is responsible for this non-expression of IgG3. Immunodeficiency was not associated with this IgG3 deficiency. Selective deficiencies of immunoglobulin classes/subclasses in experimental animals are rare. The evolution of a similar IgG3 deficiency in these three hamster strains during inbreeding suggests a novel and efficient mechanism for regulation of IgG3 synthesis in the Syrian hamster.

Membrane currents controlled by physical forces in cultured mesangial cells.

Mechanically-activated ion channels (MACs) of cultured rat mesangial cells were stimulated by applying suction to patch pipets or by exposing cells to hypoosmotic media. MAC density was estimated as 1.5 +/- 0.4 per mu 2. In the absence of any stimulus, MAC open probabilities (N * P) were < 0.0001 increasing as a function of stretch or extracellular hypoosmolarity. Single channel mean open time during stretch increased with patch depolarization whereas hyperpolarization of the membrane delayed MAC inactivation. Ionic conductance of MACs, based on average slope conductances at hyperpolarized potentials, was 76 pS in high external K+ (N = 5) and 40 pS in high external Na+ (N = 8). PK+/PNa+ was estimated to be 4.7. MACs did not permeate Cl-, at least outwardly. Whole cell currents in response to voltage steps applied to resting cells in control conditions were approximately ohmic between -120 mV and 40 mV and were linearly and reversibly dependent on extracellular osmolarity. Our results demonstrate that: (1) MACs can be activated by both negative hydrostatic pressures applied to the pipet and by osmotic gradients; (2) MAC kinetic behavior is sensitive to membrane potential; (3) MACs may participate in cellular responses to physical forces.

An ELISA system for evaluating antiretroviral activity against Rauscher murine leukemia virus.

A system for evaluating the activity of antiviral agents against Rauscher murine leukemia virus (R-MuLV) has been developed using an enzyme linked immunosorbent assay technique. The activity of various antiviral compounds demonstrated in this assay system has been compared to their activity in the UV-XC plaque reduction assay, which has been used historically for evaluating anti-R-MuLV compounds. The assay is based upon detection of R-MuLV encoded p30 protein production in virus infected murine cells. The assay reagents are readily available and the assay system is amenable to automated data collection systems. Cytotoxicity evaluations are conducted in parallel to the Rauscher MuLV ELISA assay in order to assess drug-induced reductions in cell viability. Cytotoxicity evaluations are important to interpretation of the ELISA results since reductions in cell viability reduce viral protein production which would indicate an antiviral drug effect. This system is less sensitive than the classical UV-XC plaque reduction assay; however, it does offer an alternative to the time-consuming and labor-intensive plaque assay.